title: MAIT recognition of a stimulatory bacterial antigen bound to MR1.
abstract: MR1-restricted mucosal-associated invariant T (MAIT) cells represent a subpopulation of αβ T cells with innate-like properties and limited TCR diversity. MAIT cells are of interest because of their reactivity against bacterial and yeast species, suggesting that they play a role in defense against pathogenic microbes. Despite the advances in understanding MAIT cell biology, the molecular and structural basis behind their ability to detect MR1-Ag complexes is unclear. In this study, we present our structural and biochemical characterization of MAIT TCR engagement of MR1 presenting an Escherichia coli-derived stimulatory ligand, rRL-6-CH2OH, previously found in Salmonella typhimurium. We show a clear enhancement of MAIT TCR binding to MR1 due to the presentation of this ligand. Our structure of a MAIT TCR/MR1/rRL-6-CH2OH complex shows an evolutionarily conserved binding orientation, with a clear role for both the CDR3α and CDR3β loops in recognizing the rRL-6-CH2OH stimulatory ligand. We also present two additional xenoreactive MAIT TCR/MR1 complexes that recapitulate the docking orientation documented previously, despite having variation in the CDR2β and CDR3β loop sequences. Our data support a model by which MAIT TCRs engage MR1 in a conserved fashion, with their binding affinities modulated by the nature of the MR1-presented Ag or diversity introduced by alternate Vβ usage or CDR3β sequences.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637;
authors.forename: Jacinto
authors.initials: J
authors.lastname: López-Sagaseta
authors.forename: Charles L
authors.initials: CL
authors.lastname: Dulberger
authors.forename: Amanda
authors.initials: A
authors.lastname: McFedries
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Adams
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology* / Q000648:ultrastructure; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes / Q000648:ultrastructure*; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D012486:Salmonella typhimurium / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D015395:Histocompatibility Antigens Class I; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes; D016693:Receptors, Antigen, T-Cell, alpha-beta